Endometriosis, the pathologic endometrium-like tissue on pelvic organs, develops and persists in part due to defective apoptosis and is associated with pelvic pain and infertility. During the previous funding period, we showed that retinoic acid (RA) induces endometrial expression of HSD17B2, an enzyme responsible for inactivating estradiol. Estradiol is a critical mitogen for endometriosis that is deficient of HSD17B2. A genome-wide gene expression profiling indicated strikingly lower expression of multiple RA-related genes in endometriotic tissue compared with matched endometrium: STRA6, a membrane receptor responsible for retinol (vitamin A) uptake, and CRABP2, which channels cytosolic RA to its nuclear receptor RAR1 to enhance apoptosis and reduce proliferation, were expressed at severely lower levels in endometriosis vs. endometrium. We find that these genes are primarily expressed in endometrial stromal cells and regulated by progesterone receptor (PR). We provide functional evidence that retinol and RA levels and expression of RA-target genes are significantly lower in endometriotic compared with endometrial stromal cells. Our overall hypothesis is that RA production and action is deficient in endometriosis compared with normal endometrium. This is responsible for deficient inactivation of estradiol and enhanced survival leading to persistence of endometriosis. The following aims will be pursued using established human and baboon experimental model systems of endometriosis. 1) To determine whether strikingly lower levels of STRA6 result in deficient RA production and action in endometriotic compared with normal endometrial stromal cells. We will test the hypothesis whether PR-dependent expression of STRA6 regulates retinol uptake leading to normal RA production in normal endometrial stromal cells, whereas reduced STRA6 expression causes RA deficiency and enhanced survival in endometriotic stromal cells. 2) To define the pathologic consequences of CRABP2 deficiency in human endometriotic stromal cells. We will test the hypothesis whether CRABP2 is necessary for RA/RAR1-dependent apoptosis and inhibition of proliferation in endometrial stromal cells, whereas in its absence, RA enhances cell survival via an alternative pathway. 3) To define the in vivo roles of the key genes for RA production and action in the baboon endometriosis model. We will test the hypothesis whether the key genes for RA production and RAR1-targeted action are expressed in a cycle-dependent manner in normal endometrium and significantly reduced in eutopic endometrium of baboons with endometriosis and severely deficient in pelvic endometriotic implants, where cell survival is predominant. PUBLIC HEALTH RELEVANCE: Five to ten million US women are estimated to suffer from endometriosis that causes pelvic pain and infertility. After standard treatments, symptoms usually recur within 2 years; thus, there is a clear need for research. Here, we focus on mechanisms conferring resistance to natural death of endometriosis tissue due to specific deficiencies in retinoic acid production and action. Uncovering molecular mechanisms underlying endometriosis may eventually lead to development of new therapeutic compounds that interact with novel targets.